Pre-clinical validation of AAV gene therapy for KCNV2 retinopathy improves visual function and expression in mouse...

Voltage-gated (Kv) potassium channels are critical for neuronal physiology, and their dysfunction can have serious implications. For example, mutations in the silent modulatory Kv8.2 subunit are known to cause irreversible inherited blindness (KCNV2 retinopathy). This is a currently incurable condition that causes lifelong visual loss, reduced visual acuity, photophobia, night blindness, and abnormal color vision, alongside a distinctive supernormal electrophysiological (electroretinography [ERG]) retinal response to light. In this study, we demonstrate that adeno-associated virus (AAV)-mediated gene replacement therapy delivering a codon-optimized human KCNV2 gene subretinally into Kv8.2 knockout mice significantly restores retinal function. Treated mice exhibited improved ERG responses and correct expression of KCNV2 and its encoded Kv8.2 protein in photoreceptors. Recovery of visually guided scotopic and photopic optomotor reflex responses to wild-type levels was achieved even at lower vector doses, highlighting dose-dependent efficacy. Furthermore, treatment of human retinal organoids derived from a KCNV2 patient-derived induced pluripotent stem cell (iPSC) line resulted in substantial Kv8.2 protein rescue. This work provides the preclinical proof of concept for the safety and therapeutic potential of gene therapy for KCNV2 retinopathy, laying a strong foundation for future clinical trials.